Global and regional epigenetic changes have been implicated in a growing number of human diseases including various cancers, rheumatic and autoimmune diseases, as well as congenital and hereditary disorders. Epigenetics is also rapidly gaining attention is cardiovascular biology. Focal epigenetic changes in specific genes have been implicated in the age-dependent development of atherosclerosis and in the fetal programming of hypertension. This application is based on the hypothesis that epigenetic changes in the gene for p66shc, a protein that promotes vascular oxidative stress and decreases vascular nitric oxide, contribute to the pathogenesis of endothelium-dependent vascular dysfunction. It will characterize the transcriptional mechanisms(s) controlling p66shc expression in the endothelium, determine the role of epigenetic changes in modulating this expression, and explore the physiological relevance of these transcriptional and epigenetic mechanisms in animal models of impaired endothelium-dependent vasomotor tone. By studying how epigenetics and transcription, in concert, regulate p66shc expression in the endothelium and vascular wall, and contribute to p66shc-mediated endothelium-dependent dysfunction of vascular tone, this application promises to take an important new step toward understanding how specific genes, and their interaction with the environment, play a part in the pathogenesis of vascular disorders. PUBLIC HEALTH RELEVANCE: In addition to alterations in gene DNA sequences, modifications of DNA epigenetic changes are now thought to contribute to a growing number of human diseases such as cancers and autoimmune disorders. We propose that epigenetic changes in p66shc, a gene that contributes to dysregulation of blood vessel function, play an important part in determining whether p66shc is expressed in blood vessels, and therefore contributes to dysfunction of such vessels.